Online dosimetric evaluation of larynx SBRT: A pilot study to assess the necessity of adaptive replanning

Abstract Purpose We have initiated a multi‐institutional phase I trial of 5‐fraction stereotactic body radiotherapy (SBRT) for Stage III–IVa laryngeal cancer. We conducted this pilot dosimetric study to confirm potential utility of online adaptive replanning to preserve treatment quality. Methods We evaluated ten cases: five patients enrolled onto the current trial and five patients enrolled onto a separate phase I SBRT trial for early‐stage glottic larynx cancer. Baseline SBRT treatment plans were generated per protocol. Daily cone‐beam CT (CBCT) or diagnostic CT images were acquired prior to each treatment fraction. Simulation CT images and target volumes were deformably registered to daily volumetric images, the original SBRT plan was copied to the deformed images and contours, delivered dose distributions were re‐calculated on the deformed CT images. All of these were performed on a commercial treatment planning system. In‐house software was developed to propagate the delivered dose distribution back to reference CT images using the deformation information exported from the treatment planning system. Dosimetric differences were evaluated via dose‐volume histograms. Results We could evaluate dose within 10 minutes in all cases. Prescribed coverage to gross tumor volume (GTV) and clinical target volume (CTV) was uniformly preserved; however, intended prescription dose coverage of planning treatment volume (PTV) was lost in 53% of daily treatments (mean: 93.9%, range: 83.9–97.9%). Maximum bystander point dose limits to arytenoids, parotids, and spinal cord remained respected in all cases, although variances in carotid artery doses were observed in a minority of cases. Conclusions Although GTV and CTV SBRT dose coverage is preserved with in‐room three‐dimensional image guidance, PTV coverage can vary significantly from intended plans and dose to critical structures may exceed tolerances. Online adaptive treatment re‐planning is potentially necessary and clinically applicable to fully preserve treatment quality. Confirmatory trial accrual and analysis remains ongoing.


| INTRODUCTION
Squamous cell carcinoma of the larynx is common in North America. 1 Organ preservation with chemoradiotherapy represents standard-of-care for locally advanced disease. 2,3 Conventional techniques deliver 70 Gy over 7 weeks with incidental coverage of uninvolved larynx and healthy bystander tissues. Long-term outcomes from RTOG 91-11 demonstrated comparable larynx preservation and overall survival with sequential or concurrent chemoradiotherapy. 4 A discouraging finding from this trial was that improved organ preservation with concurrent chemoradiotherapy came at the cost of late deaths, potentially due to undetected toxicity. Since this trial, no significant advances have been made in radiation-based organ preservation strategies for advanced larynx cancer.
Accelerated hypofractionated irradiation of early-stage larynx cancer originated in Europe, with early results mirroring those achieved with conventional therapy. 5,6 Despite conventional radiation techniques, there was no difference in cure rates when reducing radiation therapy from a 5-week course down to 3 weeks. 7 Later, a British Institute of Radiology study showed equivalent survival rates and no significant differences in toxicity with either a 3-week or 6-week radiation course. 6 More recently, the Royal Marsden Hospital treated 200 patients with T1 glottic cancer to a dose of 50-52.5 Gy in 16 daily fractions, 5 matching outcomes from historical studies. Beyond patient convenience and cost-saving advantages, hypofractionated radiation therapy may improve local control rates. 8 A phase III clinical trial showed improved local control with 56.25 Gy in 25 fractions compared to 60-66 Gy in 30-33 fractions, with equivalent toxicity. 9 We have initiated a multi-institutional phase I trial of 5-fraction stereotactic body radiotherapy (SBRT) for Stage III-IVa laryngeal cancer. SBRT divides intended radiation dose into five or fewer fractions with steep dose gradients and tight treatment accuracy constraints.
Thus, SBRT employs dramatically higher daily doses than conventional therapy, and holds promise for improving outcomes for highrisk disease. For example, local control of early-stage lung cancer with conventional radiation treatment is less than 50%, while newer series employing SBRT demonstrate improved local control approximating 90%. [10][11][12] Current radiation delivery techniques are based on a planning CT scan acquired before therapy begins, without planned changes during treatment. The geometry of tumor and normal anatomy can shift significantly secondary to movement and tissue responses. Serial CT studies taken during standard treatment demonstrate that tumors can shrink by > 90% during a 7-week course of treatment, and that parotid glands can involute and shift by up to a centimeter. 13 Adaptive replanning techniques have been leveraged to correct for these changes and are evolving toward becoming a routine component of standard-of-care. 14,15 To our knowledge, there are no published reports describing dosimetric variances which take place during accelerated hypofractionated treatment of head and neck cancer. In this report, we describe post hoc calculation of dose variances and pilot validation of an online adaptive planning platform to preserve treatment quality in a series of ten patients treated on prospective institutional clinical trials formally investigating SBRT for definitive treatment of laryngeal cancer.

| METHODS
For this pilot analysis we included five patient cases (Pt# 6-10) enrolled onto an advanced stage SBRT dose searching phase I trial (NCT02464137) and five patients (Pt# 1-5) enrolled onto a separate phase I SBRT trial for early-stage disease (NCT01984502). All ten patients were treated at the same institution and their data were analyzed identically. Patient characteristics are described in Table 1.
Gross Tumor Volume (GTV) was defined as all known gross disease determined by examination, CT, MRI, and FDG-PET images. All equivocal radiographic abnormalities, such as clinically suspicious lymph nodes, were included within GTV. The Clinical Target Volumes (CTV) was defined as the GTV plus areas at risk for adjacent spreads of microscopic disease. The circumferential margin between primary GTV and its CTV was 0.5 cm. Circumferential margin around nodal  We have established a SBRT quality assurance (QA) procedure to evaluate SBRT treatment delivery. All treatment planning and treatment delivery evaluation was performed with a commercial planning system (Eclipse v.11; Varian Medical Systems, Palo Alto, CA, USA) combined with in-house software. Figure 1 illustrates a flowchart for our SBRT QA and adaptive replanning platform. All baseline SBRT treatment plans were generated in Eclipse per protocol directives. Figure 2 demonstrates images collected at specific phases along our adaptive replanning process from a representative case. Thermoplastic masks were used to immobilize patients from CT simulation to every fraction of treatment.    and disease spread outside the laryngeal cartilage indeed makes the balance between PTV coverage and OAR sparing more challenging to achieve. Figure 5 illustrates the PTV prescription dose coverage as a function of GTV volume and it shows that coverage decreases with GTV volume.
Changes in bystander dose delivery to organs at risk (OARs) are detailed in Table 4. Maximum point dose and Dmean to arytenoids, spinal cord, and parotids were well respected in all cases. Cumulative Dmax to a single carotid artery increased by 13.9 Gy (patient #3) and 6.5 Gy (patient #2) from intended doses in two patients. Dmax   19 These remain active areas of investigation for platform enhancement.

| CONCLUSIONS
Our online adaptive SBRT replanning platform appears accurate and relevant to routine clinical care. Although GTV and CTV dose coverage can be preserved with CT-based IGRT guidance throughout a course of hypofractionated treatment, PTV coverage can vary significantly from intended plans. Use of online adaptive treatment replanning is potentially necessary and clinically feasible for preserving the quality of head and neck SBRT. Formal validation of the feasibility and downstream clinical impact of adaptive replanning will require continued prospective analysis. Patient accrual, dosimetric analysis, and software refinement remain ongoing.

This project was supported by CPRIT Individual Investigator
Research Award RP150386.